According to recent World Health Organization estimates, over 200 million annual cases of malaria are reported worldwide, resulting in over 600,000 deaths (World Health Organization, 2012 World Malaria Report for the year 2010). Malaria is caused by mosquito-borne parasites, usually of the Plasmodium genus. At least four species of malaria parasites can infect humans under natural conditions: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. The species P. falciparum and P. vivax are responsible for the majority of worldwide infections. In nature, malaria parasites spread by infecting successively two types of hosts, humans and female Anopheles mosquitoes. In humans, the cycle begins with a bite from a mosquito harboring a malaria parasite. The bite can inject hundreds of sporozoites under the human skin during a blood meal. These sporozoites travel from the site of the bite to the liver. They multiply in liver cells as well as in red blood cells. In the blood, successive broods of parasites grow inside the red blood cells and destroy them, releasing daughter parasites (merozoites) that continue the cycle by invading other red blood cells. The blood stage parasites cause the symptoms of malaria. When certain forms of blood stage parasites (‘gametocytes”) are picked up by a female Anopheles mosquito during a blood meal, they start another, different cycle of growth and multiplication in the mosquito. After 10-18 days, the parasites are found (as “sporozoites”) in the mosquito's salivary glands. When the mosquito takes a blood meal on another human, the infection cycle is repeated [D. Wyler, “Plasmodium and Babesia”, Chapter 287, p. 2407, in Gorbach, Bartlett & Blacklow, “Infectious Diseases, 2.sup.nd Edition, Sunders Press, 1992].
Efforts have been made to develop effective controls against the mosquito vector through the use of pesticides, but these have led to the development of pesticide-resistant mosquitoes. Similarly, the use of antiparasitic drugs (e.g., to control the Plasmodium microbe) has led to drug-resistance parasites. As the pesticidal and parasiticidal approaches have failed, focus has moved to vaccine development as an alternative. However, the complex parasitic life cycle has confounded efforts to develop efficacious vaccines, and consequently the FDA has not approved any malaria vaccine.
Apical Membrane Antigen-1 (AMA-1) is a protein that has an essential role in malaria merozoite invasion in host red blood cells. Initial vaccines containing AMA-1 from a single strain showed some protection; however, this protection was only observed against a strain that was homologous to the vaccine strain. The lack of protection against non-vaccine (divergent) strains, has made it difficult to produce a globally effective AMA-1 vaccine, given that hundreds if not thousands of strains are found in nature. Typically, vaccines against pathogens that exhibit antigenic diversity need to include multiple components directed to the different pathogenic strains. However, the extreme diversity in AMA-1 (with over 200 prevailing haplotypes) has precluded its successful implementation in a multivalent vaccine strategy. [See Takala S. L., et al., (2009) Extreme Polymorphism in a Vaccine antigen and risk of clinical malaria: Implications for vaccine development. Science Translational Med 1: 10; Polley S. D., and Conway D. J., (2001) Strong diversifying selection on domains of the Plasmodium falciparum apical membrane antigen 1 gene. Genetics 158: 1505-1512.]. Prior attempts to generate monovalent or divalent vaccines have resulted in no protection against diverse strains circulating in the field (Ref: Thera and Dicko). Accordingly, there is a need for a vaccine that protects against multiple strains of the malaria parasite and provides strain-transcending immunity against the rapidly growing blood stage of the parasite. Such vaccines can reduce global mortality and morbidity associated with malaria in humans.